The two common inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing, remitting conditions of the gastrointestinal tract. Association studies have identified a number of susceptibility genes for both diseases, implicating both adaptive and innate immunity in response to intestinal microbes and, for CD, the autophagy pathway in disease susceptibility. As with virtually all autoimmune and inflammatory disease, allelic variation at the HLA class I and class II loci has been associated with both UC and CD. Based on our previous work, the association of specific HLA haplotypes (eg. DRB1*0103-DQB1*0301) is particularly strong and, based on our recent GWAS, the strongest SNP association is with particular clinical subtypes (eg. medically refractory UC). The contribution of the natural killer cells (NK) in innate immunity to the risk of IBD has not been as well examined. NK cells are controlled by several gene families that encode cell surface receptors. The stimulatory and/or inhibitory KIR receptors use polymorphic epitopes on HLA class I as their cognate ligands. In a recent study of CD, we found inhibitory KIR heterozygotes (KIR2DL2/KIR2DL3) significantly associated with protection in the absence of their HLA ligand (CI), and predisposing in the presence of CI ligand homozygosity. We propose to expand this work by examining the role of HLA and KIR alleles, haplotypes and KIR gene-HLA ligand pairs with clinically well-defined CD and UC cohorts of Caucasian and Hispanic-Puerto Rican ancestry. We will use our newly developed Roche 454 GS FLX sequencing system for allelic HLA resolution, and will finish development and validation on our KIR (16 gene) 454 assays to sequence both gene complexes in our cohorts. Caucasian (1300 patients/550 controls and 100 family trios) and Puerto Rican (300 patients/200 controls) CD cohorts, and Caucasian (300 patients with medically refractory disease/550 controls) and Puerto Rican (200 patients/200 controls) UC cohorts will be examined. We will also develop bioinformatic tools to deal with the complex analysis of the highly polymorphic HLA and KIR genes, and make these data management and analysis tools available through NIAID's ImmPort in partnership with BISC.